JUPITER: C-reactive Protein a Marker for CV Events?

Pharmacology Watch

In this issue: The JUPITER trial causes a stir; ACP practice guideline for antidepressant use; testosterone for low libido; continued shortage of Hib vaccine; FDA Actions.

The JUPITER trial causes a stir

Elevated high-sensitivity C-reactive protein (CRP) may help identify otherwise healthy patients with normal cholesterol levels who will benefit from statin therapy, according to the JUPITER trial published in November. Researchers randomized nearly 18,000 healthy men and women with normal cholesterol levels (LDL < 130 mg/dL) with CRP levels of 2.0 mg/L or greater to rosuvastatin (Crestor®) 20 mg daily or placebo. The combined primary endpoint was myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular cause. The trial was stopped early at 1.9 years when the rate of the primary endpoint was found to be 0.77 per 100 person-years in the treatment group vs 1.36 per 100 person-years in the placebo (HR 0.56; 95% CI, 0.46-0.69; P < 0.00001). Overall, the rate of events was low in both groups: 142 of 8901 in the treatment group vs 251 of 8901 in the placebo group. The individual endpoints of myocardial infarction, stroke, and revascularization or unstable angina were all reduced by approximately 50% in the rosuvastatin group, LDL cholesterol levels were decreased by 50%, and CRP levels were decreased 37%. There was not a significant increase in myopathy or cancer in the treatment group, but there was a higher incidence of physician-reported diabetes. The authors conclude that in apparently healthy persons without hyperlipidemia but with elevated CRPs, rosuvastatin significantly reduced the incidence of major cardiovascular events (N Engl J Med 2008;359:2195-2207).

In an accompanying editorial, Mark Hlatky, MD, Stanford University School of Medicine, points out that although the relative risk reductions in the JUPITER trial were clearly significant, the absolute difference in risk was less impressive with 120 participants treated for 1.9 years to prevent one event. It is also difficult to know the role of CRP in risk stratification since patients with normal CRP levels were not treated and it is possible that lowering cholesterol with statins may benefit even those with low CRP levels. CRP may have a role in deciding whether to treat patients with intermediate risk, but it may be too early to use it to recommend treatment for those at low risk. Hlatky writes that "guidelines for primary prevention will surely be reassessed on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and long-term safety and cost" (N Engl J Med 2008;359:2280-2282). It is safe to say that JUPITER has been the subject of many lively discussions in hospital lunchrooms across the country. Whether the benefit of rosuva-statin can be generalized to all statins, whether CRP should be a standard part of yearly blood panels for adults patients, and whether everyone with an elevated CRP should be offered treatment with a statin are all questions that are being hotly debated and will need further evaluation.

ACP treatment guideline for antidepressants

The American College of Physicians has issued a practice guideline for the use of antidepressants to treat depressive disorders. The guideline encompasses the use of newer "second-generation antidepressants," including the SSRIs: fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), citalopram (Celexa®), escitalopram (Lexapro®), and fluvoxamine (Luvox®). Also included were the SNRIs venlafaxine (Effexor®), and duloxetine (Cymbalta®), as well as other drugs such as mirtazapine (Remeron®), bupropion (Wellbutrin®), nefazodone, and trazadone. After reviewing 203 clinical trials, the guideline group concluded that there were no significant differences between the drugs with regard to efficacy. The guideline group recommends that second-generation antidepressants should be selected on the basis of adverse effect profiles, cost, and patient preference. They further recommend that clinicians should assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1-2 weeks of initiation of therapy and that treatment should be modified if the patient does not have an adequate response to pharmacotherapy within 6-8 weeks. Finally, they recommend that clinicians continue treatment for 4-9 months after a satisfactory response in patients with a first episode of major depressive disorder. For patients with history of depression, a longer duration of therapy may be beneficial (Ann Intern Med 2008;149:725-733).

Testosterone for low libido: Questions remain

Low sexual desire is commonly reported by postmenopausal women. A new study suggests that testosterone replacement may be of benefit. Researchers randomized 814 postmenopausal women with hypoactive sexual desire or disorder to testosterone patches delivering 150 or 300 µg of testosterone per day or placebo. The primary endpoint was change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. Safety outcomes were followed out to one year. At 24 weeks the primary endpoint was significantly greater in the group receiving 300 µg of testo-sterone per day than placebo (increase in sexually satisfied episodes of 2.1 vs 0.7, P < 0.001) but not in the group receiving 150 µg per day. Both doses of testosterone were associated with significant increases in desire and decreases in distress. The rate of androgenic side effects including unwanted hair growth was higher in the group receiving 300 µg per day. Breast cancer was diagnosed in 4 women who received testosterone vs none in the placebo group. The authors conclude that a testo-sterone patch delivering 300 µg per day results in modest but meaningful improvement in sexual function although the long-term effects of testo-sterone including effects on the breasts remain uncertain (N Engl J Med 2008;359:2005-2017). This study confirms previous reports that testosterone has a positive effect on sexuality in women. The rate of breast cancer, although not reaching statistical significance in this study, raises concern.

Continued shortage for Hib vaccine

The continued shortage of the Haemophilus influenza type b (Hib) vaccine has not led to an increase in Haemophilus infections according to the MMWR. It has been a year since the CDC recommended deferring the fourth dose of the Hib vaccine in healthy children (at 12-15 months of age) because of a shortage due to contamination concerns in the manufacturing process. Merck & Co. now reports that mid-2009 is a realistic date for normal production. The CDC has undertaken national surveillance for Hib infections including 748 cases in children < 5 years old. Of these, only 6% were clearly identified as serotype b (the most invasive strain of Haemophilus), although serotyping information was missing in nearly 40% of cases. The CDC is concerned because antibody levels fall 12 months after vaccination in children. In the U.K., where the fourth booster was not initially recommended, Hib infections rebounded after 12-15 months. CDC is recommending vigilance on the part of pediatricians and also is emphasizing that state and hospital labs should perform serotyping on all Haemophilus infections.

FDA Actions

The FDA has approved fesoterodine fumarate for the treatment of overactive bladder. The drug relaxes smooth muscle of the bladder reducing urinary frequency, urge to urinate, and sudden urinary incontinence. Fesoterodine fumarate will be available in 4 mg and 8 mg strengths for use once daily. The drug is manufactured by Schwartz Pharma and will be marketed as Toviaz™.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: paula.cousins@ahcmedia.com.